The prevalence of overweight and obesity and associated comorbidities in the human population has increased at an unprecedented rate in recent years. The United Nations has estimated that if this trend continues, 17% of adults globally will be obese by 2025. That is, there will be 170 million adults with a BMI >35. If the estimate also adds overweight population, there will be 2.7 billion overweight adults by 2025, well above the 2 billion of 2010.
Type 2 diabetes mellitus is one the greatest impact comorbidities associated with overweight and obesity. It has been estimated that the number of adults with diabetes has almost quadrupled from 108 million adults who had diabetes in the year 1980 to 422 million adults in 2014. Diabetic complications can lead to heart attacks, blindness, renal failure or limb amputation, among other consequences. It is believed that 43% of premature deaths (before age 70) occurring due to diabetes are preventable by the adoption of policies supporting a healthy life style, as well as through improved methods of detection and treatment of the illness.
Consequently, there is a global commitment to prevent, detect and treat overweight and obesity, and associated comorbidities, since these diseases have profound physical, psychological and socioeconomic impacts.
The active ingredient tesofensine, (3S,4R)-3-(3,4-dichlorphenyl)-4-(ethoxymethyl)-8-methyl-8-azabicyclo[3.2.1]octane, first described in WO 97/30997, is a monoamine reuptake inhibitor. WO 97/30997 suggests that tesofensine may be used to treat obesity. It has been taught that tesofensine has the potential to produce weight loss at a better rate than currently approved drugs. It has also been found that tesofensine has the potential to reverse the progress of type 2 diabetes mellitus by decreasing hepatic fat, and also has beneficial effects on plasma insulin concentration and glycated hemoglobin (HbAlc) (U.S. Pat. No. 8,202,884 B2; Astrup A, Madsbad S, Breum L, Jensen T, Kroustrup J and Meinert T (2008) Lancet 372(9653): 1906-13; Wharton S and Serodio K (2015) Curr Cardiol Rep. 17(5):35). WO 2005/073228 describes isolation, purification and large scale production of tesofensine.
Preclinical and clinical studies conducted with tesofensine have increased the knowledge on the drug's mechanism of action and have generated new findings regarding its use for treating conditions of overweight, obesity and type 2 diabetes mellitus.
The prior art has also taught the doses at which tesofensine would provide the desired therapeutic effects, and has disclosed compositions of tesofensine in combination with other active ingredients such as metoprolol (WO 2013/120935).
One skilled in the art would know that establishing the stability of a pharmaceutical composition is a determining factor since the chemical stability of pharmaceutical molecules can affect the safety and efficacy of a medicament. Testing the stability of a pharmaceutical product is essential to understand how the quality of the drug and that of the final product changes over time under several environmental conditions. Applicants are required to observe this prerequisite to obtain a marketing authorization.
Evaluation of the drug's stability is critical to achieve safe and effective formulations and pharmaceutical forms, as well as to select proper packaging. On the other hand, the dissolution profile is a key indicator of the quality and is inherently related with the selection of the proper excipients as well as with the selection of the manufacture equipment and best preparation methods.
In view of the potential of tesofensine in medicine, it would be advantageous to have qualitative and quantitative formulations of tesofensine. It would also be advantageous if such pharmaceutical formulations were sufficiently stable and effective so that they can be used commercially to prepare medicaments indicated for the prevention and treatment of overweight, obesity and type 2 diabetes mellitus. Specifically, it would be advantageous to identify pharmaceutical compositions showing bioavailability and chemical stability, and a low content of impurities. It is also desirable to obtain orally administerable, commercial, pharmaceutical tesofensine compositions, without compromising bioavailability or stability.